1. Field of the Invention
The present invention relates to substituted thiazolesulfonamides that have carbonic anhydrase inhibition (CAI) activity and are useful as anti-glaucoma agents.
2. Background of the Art
Glaucoma is an ocular disorder associated with elevated intraocular pressures which are too high for normal function and may result in irreversible loss of visual function. If untreated, glaucoma may eventually lead to blindness. Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic nerve head damage or characteristic glaucomatous visual field defects, is now believed by many ophthalmologists to represent the earliest phase of glaucoma.
Many of the drugs formerly used to treat glaucoma proved not entirely satisfactory. Indeed, few advances were made in the treatment of glaucoma since pilocarpine and physostigmine were introduced. Only recently have clinicians noted that many .beta.-adrenergic blocking agents are effective in reducing intraocular pressure, they also have other characteristics, e.g. membrane stabilizing activity, that are not acceptable for chronic ocular use. (S)-1-tert-Butylamino-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propan ol, a .beta.-adrenergic blocking agent, was found to reduce intraocular pressure and to be devoid of many unwanted side effects associated with pilocarpine and, in addition, to possess advantages over many other [3-adrenergic blocking agents, e.g., to be devoid of local anesthetic properties, to have a long duration of activity, and to display minimal tolerance.
Although pilocarpine, physostigmine and the .beta.-adrenergic blocking agents mentioned above reduce intraocular pressure, none of these drugs manifests its action by inhibiting the enzyme carbonic anhydrase and, thereby, impeding the contribution to aqueous humor formation made by the carbonic anhydrase pathway.
Agents referred to as carbonic anhydrase inhibitors, block or impede this inflow pathway by inhibiting the enzyme, carbonic anhydrase. While such carbonic anhydrase inhibitors are now used to treat intraocular pressure by oral, intravenous or other systemic routes, they thereby have the distinct disadvantage of inhibiting carbonic anhydrase throughout the entire body. Such gross disruption of a basic enzyme system is justified only during an acute attack of alarmingly elevated intraocular pressure, or when no other agent is effective.
Topically effective carbonic anhydrase inhibitors are reported in U.S. Pat. Nos. 4,386,098; 4,416,890; and 4,426,388. The compounds reported therein are 5 (and 6)-hydroxy-2-benzothiazolesulfonamides and acyl esters thereof. Furthermore, U.S. Pat. No. 4,544,667 discloses a series of benzofuran-2-sulfonamides, and U.S. Pat. Nos. 4,477,466; 4,486,444; 4,542,152; and 4,585,787 disclose 5-phenylsulfonylthiophene-2-sulfonamides and 5-benzoylthiophene-2-sulfonamides and alkanoyloxy derivatives thereof which are reported to be topically effective carbonic anhydrase inhibitors useful in the treatment of elevated intraocular pressure (IOP) and glaucoma.
Additionally, U.S. Pat. No. 4,914,111 reports that thiophene or furan-2-sulfonamides, having a 4-benzyl substituent are effective for the topical treatment of elevated intraocular pressure and glaucoma. And another application assigned to Allergan by the same inventor (patent application Ser. No. 07/939,189, filed Jul. 2, 1992) describes the preparation and utility of 3-thiophenesulfonamide compounds in the treatment of elevated intraocular pressure (IOP) and glaucoma.
Finally, U.S. Pat. No. 2,994,701 discloses 2-sulfamyl-4-substituted thiazoles having diuretic activity on systemic administration.
In view of the above, it is clear that a great deal of research has been carried out on the use of sulfonamides for the topical treatment of glaucoma. However, the use of the substituted 2- and 5-thiazole sulfonamides has not been suggested for use in the topical treatment of glaucoma.
Therefore, one object of this invention is to provide novel substituted 2- and 5-thiazole sulfonamides.
It is another object of this invention to provide compounds having carbonic anhydrase inhibition activity.
Another object of this invention is to provide a method of inhibiting carbonic anhydrase activity to thereby treat elevated intraocular pressure (IOP) and glaucoma.
A further object of this invention is to provide CAI inhibitory compounds which have little or cysteine reactivity and hence little sensitization potential when administered to the eye.
Other objects and advantages of the instant invention will become apparent from a careful reading of the specification below.